The goals of our Center, """"""""Modifiers of FMR1-associated disorders: application of high throughput technologies"""""""", are targeted to the RFA research area to Advance the understanding of the pathophysiology of FMR1 Related Conditions. The completion of the proposed aims from the three research projects will lead to the identification of the genetic basis of variable expressivity or incomplete penetrance of FMR1- associated conditions. Project A will focus on the variable expression of epilepsy among boys with Fragile X syndrome (FXS), a co-morbid condition that occurs among 15% of affected boys and we speculate that variation elsewhere in the genome is responsible. Likewise, Project B will focus on the incomplete penetrance of Fragile X tremor/ataxia syndrome (FXTAS) in men, a neurodegenerative disorder among those with the permutation (PM), with a lifetime prevalence of 30% among males. Project C focuses Fragile X association primary ovarian insufficiency (FXPOI), which manifests in 20% of PM carriers as premature ovarian failure (POF), or cessation of menses prior to age 40. POF leads to infertility and estrogen-deficiency related disorders usually reserved for the aged. Our goal is to identify and understand the extent of the epistemic effects of modifying genes on these three Mendelian disorders. The Center will include three projects and two shared cores, all administered by an Administrative Core. Each proposed research project will take the same novel approach to define a set of candidate genes for further study in mammalian systems. They will: 1) use the Recruitment Core B to ascertain the 100 cases and 100 controls drawn from extreme phenotypic tails of each disorder, 2) conduct whole genome sequencing on each of the 100/100 cases/controls series using the expertise and experience of the Genomics and Analytical Core C, and 3) after validating variants, assess the function of prioritized genes using the established phenotypic assays in the corresponding Drosophila models. The research we propose in our Center is highly innovative, using cutting-edge technologies, to answer fundamental questions related to Fragile X-related disorders. All Center investigators are part of Emory University, an institution with possibly the largest group of independent faculty working on Fragile X-related disorders and with nearly a 30-year history of contributions to the field. Moreover, an added synergy and excitement within this Center is driven by the common theme among all the projects, ensuring a highly interactive and productive research environment.

Public Health Relevance

The identification of genes whose variation modifies the phenotype of a Mendelian disorder is emerging at the forefront of contemporary human genetics. Characterizing those modifying genes for Fragile X syndrome associated epilepsy, Fragile X-associated ovarian insufficiency and Fragile X-associated tremor/ataxia syndrome will increase the understanding of perturbed pathways involved in these disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
1U54NS091859-01
Application #
8793381
Study Section
Special Emphasis Panel (ZHD1-DSR-Y (53))
Program Officer
Mamounas, Laura
Project Start
2014-09-22
Project End
2019-05-31
Budget Start
2014-09-22
Budget End
2015-05-31
Support Year
1
Fiscal Year
2014
Total Cost
$1,806,933
Indirect Cost
$638,950
Name
Emory University
Department
Genetics
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Kotlar, Alex V; Trevino, Cristina E; Zwick, Michael E et al. (2018) Bystro: rapid online variant annotation and natural-language filtering at whole-genome scale. Genome Biol 19:14
Yao, Bing; Li, Yujing; Wang, Zhiqin et al. (2018) Active N6-Methyladenine Demethylation by DMAD Regulates Gene Expression by Coordinating with Polycomb Protein in Neurons. Mol Cell 71:848-857.e6
Sun, Xiaobo; Gao, Jingjing; Jin, Peng et al. (2018) Optimized distributed systems achieve significant performance improvement on sorted merging of massive VCF files. Gigascience 7:
Bienkowski, Rick S; Banerjee, Ayan; Rounds, J Christopher et al. (2017) The Conserved, Disease-Associated RNA Binding Protein dNab2 Interacts with the Fragile X Protein Ortholog in Drosophila Neurons. Cell Rep 20:1372-1384
Albizua, Igor; Rambo-Martin, Benjamin L; Allen, Emily G et al. (2017) Women who carry a fragile X premutation are biologically older than noncarriers as measured by telomere length. Am J Med Genet A 173:2985-2994
Li, Liping; Zang, Liqun; Zhang, Feiran et al. (2017) Fat mass and obesity-associated (FTO) protein regulates adult neurogenesis. Hum Mol Genet 26:2398-2411
Anderson, Bart R; Chopra, Pankaj; Suhl, Joshua A et al. (2016) Identification of consensus binding sites clarifies FMRP binding determinants. Nucleic Acids Res 44:6649-59
Espinel, Whitney; Charen, Krista; Huddleston, Lillie et al. (2016) Improving Health Education for Women Who Carry an FMR1 Premutation. J Genet Couns 25:228-38
Xie, Nina; Gong, He; Suhl, Joshua A et al. (2016) Reactivation of FMR1 by CRISPR/Cas9-Mediated Deletion of the Expanded CGG-Repeat of the Fragile X Chromosome. PLoS One 11:e0165499
Hipp, Heather S; Charen, Krista H; Spencer, Jessica B et al. (2016) Reproductive and gynecologic care of women with fragile X primary ovarian insufficiency (FXPOI). Menopause 23:993-9

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